撰文丨王聪 编辑丨王多鱼 排版丨水成文 系统性红斑狼疮 （SLE） 是一种慢性自身免疫疾病，其特征是产生靶向多个器官系统的自身抗体，从而导 致多样的临床表现以及较高的发病率和死亡率。尽管包括皮质类固醇、免疫抑制剂和生物制剂在内的疗法 有所进步，但许多 难治性系统性红斑狼疮 （rSLE） 患者对常规治疗仍反应不佳，这凸显了开发新型治疗 策略的必要性。 目前，美国 FDA 已批准了多款 CAR-T 细胞疗法 用于治疗血液系统癌症，这些疗法要么靶向 CD19，要么 靶向 BCMA。自 2021 年以来，已有多项研究报道了 靶向 CD19 的CAR-T 细胞疗法 在系统性红斑狼疮等 自身免疫疾病中的有效性和安全性，然而将其与 靶向 BCMA 的 CAR-T 细胞疗法 相结合的研究，仍十分 有限。 近日，浙江大学医学院附属第一医院 黄河 教授、 胡永仙 教授、 刘志宏院士、林进 主任 医师、 浙江大学 医学院附属邵逸夫医院 鲁林荣 教授、复旦大学/上海雅科生物 张鸿声 博士作为共同通讯作者 （ 冯晶晶、 霍大伟、洪睿敏、金雪潇、曹恒、邵谧、温睿为论文共同第一作者 ） ，在 Nature Medicine 期刊在线发 表 ...

Core Viewpoint - The study published in Science Translational Medicine highlights the role of the m6A demethylase FTO in the proliferation of age-associated B cells (ABC) and its connection to kidney damage in systemic lupus erythematosus (SLE), suggesting potential therapeutic targets [2][4][10]. Group 1: Mechanism of SLE and ABC Proliferation - The research identifies that the expansion of ABC in SLE is mediated by the m6A demethylase FTO, linking it to kidney damage [4]. - FTO is found to be highly expressed in ABC of SLE patients, with its expression positively correlated with immune damage in the kidneys [8]. - Overexpression of FTO in mouse and human B cells promotes ABC expansion and exacerbates SLE, while FTO deficiency improves autoimmune responses driven by ABC [9]. Group 2: TLR7-FTO-ATP6V1G1 Signaling Pathway - The study reveals that activation of the TLR7-MyD88 signaling pathway upregulates FTO expression, which in turn targets ATP6V1G1 in an m6A-dependent manner, promoting TLR7-driven ABC differentiation [9][10]. - FTO deficiency impairs lysosomal autophagy by reducing V-ATPase activity mediated by ATP6V1G1, leading to mitochondrial dysfunction in B cells [10]. - The accumulation of damaged mitochondria results in decreased oxidative phosphorylation and increased reactive oxygen species levels, inhibiting cell proliferation and ABC differentiation [10].

科技日报讯 （记者江耘 通讯员周炜）9月30日，记者从浙江大学良渚实验室获悉，该实验室研究团队首 次证实人类单个基因PLD4的缺陷可导致系统性红斑狼疮，并阐明其致病机制，为系统性红斑狼疮的精 准诊疗提供了重要理论依据。相关研究日前发表在国际期刊《自然》上。 系统性红斑狼疮的确切发病机制尚未完全明确，遗传因素与免疫异常在其发生发展中起关键作用。 此次研究发现了能导致系统性红斑狼疮的单基因，为深入理解系统性红斑狼疮发病的分子机制，开发靶 向治疗策略提供崭新视角。目前，科学界已陆续鉴定出30余种由单个基因突变导致的系统性红斑狼疮。 来源：科技日报 为了揭示PLD4基因缺陷在系统性红斑狼疮中的致病机制及其主要效应免疫细胞群，研究团队构建了相 同基因缺陷的小鼠模型。结果显示，缺陷小鼠表现出典型的狼疮样表型。多组织炎症分析显示，肾脏是 缺陷小鼠受累最为显著的器官，与人类患者的临床肾脏表型高度一致。 【医线传真】 研究团队采用JAK抑制剂巴瑞替尼对缺陷小鼠进行干预，发现巴瑞替尼可显著缓解缺陷小鼠的狼疮样表 型。巴瑞替尼还在患者来源的炎症细胞中有效抑制了Ⅰ型干扰素通路的过度激活，为治疗PLD4基因缺 陷所致系统性红斑狼疮提供 ...

Core Insights - The article discusses the complex medical case of a 56-year-old woman suffering from multiple health issues, including myasthenia gravis and complications from a colon perforation, which required advanced surgical intervention [1][3][4]. Group 1: Patient Condition and Initial Treatment - The patient, suffering from myasthenia gravis, experienced a spontaneous colon perforation leading to severe infections and complications post-surgery, including colostomy-related issues [1][3]. - Initial treatment involved abdominal washing, partial resection of the sigmoid colon, and colostomy, but resulted in further complications such as colonic fistula and severe infections [3][4]. Group 2: Surgical Intervention - The surgical team at Southeast University Affiliated Zhongda Hospital, led by Dr. Tao Qingsong, performed a complex laparoscopic surgery to address the colonic fistula and restore normal bowel function [4]. - The surgery included left hemicolectomy, adhesiolysis, colostomy reversal, and abdominal wall reconstruction, with minimal blood loss of only 100 milliliters [4]. Group 3: Post-Surgery Recovery - Post-operative care involved close monitoring in the intensive care unit, followed by a tailored rehabilitation plan to ensure recovery of bowel function and overall health [4]. - The patient showed significant improvement, was able to mobilize shortly after surgery, and did not experience any complications such as recurrent infections [4]. Group 4: Medical Insights and Recommendations - Experts highlighted that infections are a significant factor in the deterioration of myasthenia gravis, often leading to respiratory failure and swallowing difficulties [5]. - Recommendations for myasthenia gravis patients include strict hygiene practices and immediate medical attention for any signs of infection or worsening symptoms [5].

Core Insights - AstraZeneca's asthma drug Fasenra failed to control acute exacerbations in a late-stage study for chronic obstructive pulmonary disease (COPD) patients, marking a setback for the company's efforts in addressing this serious lung condition [1] - Fasenra is AstraZeneca's second-best-selling respiratory and immunology drug, with sales reaching $920 million in the first half of 2025, an 18% year-over-year increase [1] - The study participants were current or former smokers with a history of at least two acute exacerbations in the past year, and Fasenra did not meet the primary endpoint compared to placebo [1] - AstraZeneca plans to analyze the complete study data to better understand the results [1] Additional Developments - AstraZeneca's executive Sharon Barr emphasized the complexity and heterogeneity of COPD, stating the company will continue to advance other promising solutions in its pipeline to meet unmet patient needs [2] - The company has other COPD treatments, including the three-in-one inhaler Breztri Aerosphere and the investigational drug tozorakimab [2] - AstraZeneca announced that its rare disease drug Saphnelo successfully met its primary endpoint in a late-stage clinical trial, significantly reducing the activity of systemic lupus erythematosus, a chronic autoimmune disease [2]

Core Viewpoint - The research identifies loss-of-function mutations in the PLD4 gene as a cause of systemic lupus erythematosus (SLE), providing a theoretical basis for precise diagnosis and treatment of the disease [3][10]. Group 1: Research Findings - The study published in Nature confirms that mutations in the PLD4 gene can lead to SLE and elucidates the pathogenic mechanism involved [3]. - The research team reported five SLE patients with renal lesions exhibiting PLD4 biallelic mutations [8]. - PLD4 is highly expressed in dendritic cells, monocytes, and B cells, and functions as a 5' nucleic acid exonuclease that limits the overactivation of TLR7 and TLR9 [7]. Group 2: Mechanism of Action - TLR7 and TLR9 play critical roles in sensing RNA and DNA, initiating downstream inflammatory signaling pathways that contribute to SLE development [6]. - The absence of PLD4 leads to excessive activation of TLR7 and TLR9, resulting in heightened inflammatory responses and the production of autoantibodies [10]. Group 3: Potential Therapeutic Implications - PLD4-deficient mice exhibited autoimmune phenotypes and responded to the JAK inhibitor baricitinib, suggesting that targeting type I interferon may be a potential therapy for SLE patients with PLD4 deficiency [10].

Core Insights - Systemic lupus erythematosus (SLE) is a common chronic autoimmune disease with a complex pathogenesis, and a defect in the human single gene (PLD4) has been confirmed by Chinese scientists as a cause of SLE, providing important theoretical basis for precise diagnosis and treatment [1][2] Group 1 - The research team identified mutations in the PLD4 gene in five patients with lupus nephritis through whole-exome sequencing, indicating that this gene is present in dendritic cells, B cells, and monocytes, and the mutations are inherited in a recessive manner [1] - The study highlights the heterogeneity of SLE, with significant individual differences in clinical symptoms and genetic mechanisms, posing challenges to understanding its pathogenesis [1] Group 2 - The research further revealed that the PLD4 gene mutation triggers a pathogenic mechanism of chronic inflammation and autoimmunity, and experiments on mice confirmed that certain targeted therapies, such as JAK inhibitors, can significantly alleviate symptoms in mice with the defect [2] - This finding offers potential precision treatment strategies for SLE patients carrying the PLD4 mutation and provides a crucial basis for future individualized treatment based on genetic typing [2]

Core Viewpoint - The research highlights a significant breakthrough in the use of allogeneic CAR-T cell therapy for treating autoimmune diseases, specifically refractory systemic lupus erythematosus (SLE), demonstrating long-term remission and safety [2][3][4]. Group 1: Research Findings - The study published in Cell reported the successful use of allogeneic CD19-targeted CAR-T cells (TyU19) in treating refractory immune-mediated necrotizing myopathy and diffuse cutaneous systemic sclerosis, achieving long-term remission [1]. - In a subsequent study published in Med, the same CAR-T cell therapy was shown to effectively treat three patients with refractory SLE, leading to significant reductions in serum autoantibodies and achieving clinical remission as defined by the SRI-4 standard [3][6][7]. - The therapy demonstrated good tolerance, with no occurrences of graft-versus-host disease (GvHD), cytokine release syndrome (CRS), or immune effector cell-associated neurotoxicity syndrome (ICANS) reported during the study [9][10]. Group 2: Methodology and Safety - The clinical trial involved three patients with severe refractory SLE, where CAR-T cells were infused at a dose of 1 million cells per kilogram, and safety was assessed through the monitoring of potential adverse events [5][6]. - The CAR-T cells showed robust in vivo proliferation, peaking on day 14 post-infusion, and effectively eliminated B cells from the patients, leading to a significant decrease in B cell counts [6][9]. - The study utilized a low-intensity lymphocyte-depleting regimen, and even without pre-treatment lymphocyte clearance, TyU19 exhibited remarkable therapeutic efficacy, indicating a new potential pathway for treating autoimmune diseases [11].

Core Viewpoint - The study demonstrates the safety and efficacy of allogeneic CD19-targeted CAR-T cell therapy (TyU19) in treating refractory systemic lupus erythematosus (SLE), marking a significant advancement in the application of CAR-T cell therapy for autoimmune diseases [2][3][16]. Group 1: Research Background - In 2021, researchers at Erlangen-Nuremberg University successfully treated a patient with refractory SLE using CAR-T cell therapy, leading to numerous clinical trials worldwide to evaluate its safety and efficacy in B cell-mediated autoimmune diseases [2]. - Allogeneic CAR-T cells offer advantages such as uniformity, rapid availability, and potential cost-effectiveness, but face limitations due to risks like graft-versus-host disease (GvHD) and gene editing-related toxicity [2][3]. Group 2: Study Details - The study, a single-center pilot trial (NCT05988216), assessed the safety and efficacy of TyU19 in patients with refractory SLE, utilizing CRISPR-Cas9 gene editing to modify CAR-T cells from healthy donors [6][12]. - Four young female patients aged 22-24 with a history of multiple organ involvement were included, all having baseline SELENA-SLEDAI scores between 14-26 [7]. Group 3: Treatment Protocol and Results - Patients underwent a lymphocyte-depleting chemotherapy regimen before receiving a dose of 1×10^6 CAR-T cells/kg [7]. - All patients showed sustained clinical improvement, achieving a SELENA-SLEDAI score of zero and a PGA score of less than 1 within 3-6 months post-treatment [9][11]. - Symptoms such as arthritis, hair loss, and finger vasculitis resolved, and levels of complement factors C3 and C4 normalized [9]. Group 4: Safety Profile - The most common grade 3 or 4 adverse events included neutropenia, lymphopenia, and liver dysfunction, attributed to the lymphocyte-depleting pre-treatment [11]. - No patients experienced severe adverse events like immune effector cell-associated neurotoxicity syndrome (ICANS) or GvHD, and no infections occurred during the study [11][12]. Group 5: Innovative Aspects - TyU19 demonstrated a significant innovation by requiring a less intensive lymphocyte-depleting regimen compared to traditional CAR-T therapies, even exploring a "no depletion" approach [12]. - The therapy showed potential for long-term efficacy by targeting both abnormal B cells and inhibiting plasma cell regeneration, as evidenced by the reduction of BCMA+ and CD19-BCMA+ plasma cells post-treatment [15][16]. Group 6: Conclusion and Future Directions - The study highlights the potential of allogeneic CD19-targeted CAR-T cell therapy as a promising treatment for refractory SLE, warranting further research to explore its long-term efficacy and optimize its application in challenging autoimmune diseases [16].